Field of the Invention
The present invention relates to processes for the manufacture of crystalline particles of an anti-muscarinic drug. The present invention also relates to Said particles pharmaceutical formulations which contain such particles and methods for the prevention and/or treatment of respiratory diseases by administering such a formulation.
Discussion of the Background
It is known that water soluble quaternary ammonium compounds with antimuscarinic activity tend to agglomerate during storage. This is attributed to the formation of crystal bridges between neighboring particulates due to the absorption of moisture post micronization and subsequent recrystallization of surface amorphous content which is generated by the high energy micronization process. This problem particularly affects the physical stability of the drug and its subsequent performance in formulations.
Glycopyrronium is an anti-muscarinic drug commercially available as bromide salt since many years.
Glycopyrronium bromide has two chiral centers corresponding to four isomeric forms comprising two pairs of diastereoisomers, namely (3S,2′R)-, (3R,2′S)-, (3R,2′R)-, and (3S,2′S)-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide. Commercially available glycopyrronium bromide consists of the purified “threo” diastereoisomer (3R,2′S) and (3S,2′R) and is hereinafter indicated as rac-glycopyrronium bromide.
However, similarly to other anti-muscarinic agents, glycopyrronium salts have significant stability problems, especially immediately following conventional micronization processes by milling.
In fact, glycopyrronium bromide, once micronized, has a strong tendency to aggregate and/or agglomerate, which severely hinders downstream drug processing, particularly the preparation of dry powder formulations for administration by inhalation capable of delivering a good respirable fraction.
Various processes have been proposed in order to change certain physicochemical properties of the drug. However many of these processes involve the use of solvents which tend to cause local solvation processes that, in turn, lead to particle growth and/or irreversible aggregation and agglomeration during drying or storage.
In addition, it is well known that the current state-of-the-art high energy physical processing procedures, such as air jet milling, dry powder ball-milling or high pressure homogenization, give rise to a partial loss of drug crystallinity. These micronized materials are often subjected to post micronization conditioning at high temperature for long periods in order to condition out any process-induced structural disorder and/or amorphous content.
In view of these considerations, it would be highly advantageous to provide a process for preparing crystal particles of a glycopyrronium salt, physically stable, with a narrow particle size suitable for delivery by inhalation.
This problem is solved by the process of the present invention.